Certain esters of tropine and tropinium salts



United States Patent CERTAIN ESTERS 0F TROPINE AND TROPINIUM SALTS Nathan Weiner, Rego Park, and Samuel M. Gordon, Forest Hills, N.Y., assignors to Endo Laboratories, Inc., Richmond Hill, N .Y., acorpo'ration'of New York No Drawing. Filed'July 3, 1957,-S'e'r, No. 669,707 8 Claims; (Cl. 260-292) This invention relates to tropine; and in particular is directedto new esters of tropine and quarternary tropinium salts thereof, which are characterized by a surprising and remarkable stability to hydrolysis and unexpected pharmacological activity; and method -of preparing them.

The naturally occurring a kaloid atropine is the tropic acid ester of tropine of Structure I.

I cum 0110-4-0 04211-05115 I CH'rCH-CH9 I CHzOH (I) Tropine Tropic acid Atropine has the ability to block, diminish or reverse. the various physiologic actions of acetyl choline. There have been synthesized manycor'npoun'ds with activities" similar to those of atropine in some respect or*other; In general, such compounds have been esters of amino alcohols. For example, a large series of esters of tropine have been synthesized in which simple normal aliphatic acids, hydroxy aliphatic acids, aromatic'acids. and hydroxy aromatic acids have been used for the acid moiety.

These esters of tropine are in general characterized by a relative ease of hydrolysis into the-acid and tropine fragments, whereby the atropine-like action is lost. This is of great practical significance for application ofthese compounds. A common means of adm nistering these compounds is as an elixir or syrup. When so compounded, careful attention must be paid to the control of the pH of the solvent medium inorder to minimize the hydrolysis. Frequently the pH for optimum stability may be incompatible with the stability or even the presence of other pharmacological agents in the'preparation. Thus, it would become'impossible to'administer, in a syrup or elixir, a desirable combination of two synergistic pharma cologic agents in which such incompatibilities might arise. Even at the optimum pH for stability, hydrolysis will take place slowly.

The esters of our invention aremade from branched chain aliphatic acids of the following general structure- CH-COOH" in which R and R are alk yl groups containing 1 to 4 carbon atoms and R and R are drawn-from "the groups embracing hydrogen and alkyl groups' -'containing 1 to 4 2. carbon atoms. The tropinium salts of this invention thus have the structurel on on -om o E 2 11- R2 CHaN-R5 (EHO-O-Cil x- Rs 7 BA wherein R R R and R have the value. previously defined above; R is chosen from the. group of hydrogen, lower alkyl and lower aralkyl; eIg. 'benzyL'substituted benzyl, phenethyl'and substituted phenethyl; and X is the anion of anysuitable, physiologically compatible acid; Thus the compounds of this invention are inth'e' form of salts of the tertiary tropine ester base or the derived quarternary ammonium salts, where R has values other than hydrogen. Examples of the salts which can be pref pared from these esters include halide,'sulfa'te, pho'sf phate, citrate, tartrate, nitrate, methosulfate andthe like; Some of the processes by which th'ecomp'ound s ofo'ur inventions are given 'in the examples which fo'llow; ar'i'cl many'of the compounds encompassed" by this invention" are listed by'number in'Table'I. t To demonstrate the unusual stability to hydrolysis of' the novel esters, we have compared the rate of hydrolysis of homatropinemethyl bromide of the following structure oH,----on' -crn OH with the rate of hydrolysis of aselected group of the compounds of our invention.

Thus. homatropine methyl bromide in a concentration of 0.0025 molar is hydrolyzed 'at room'temperature by 0.005 molar sodium hydroxide at a 'rat'e'"such that 50% of the ester has disappeared in 2.2 minutes. Thus, the half life thereof under those conditions, is 22. minutes. When compound No. 7 of Table I is subjected tohydrolysis under the same conditions of-conceritration and temf perature, the rate of disappearance of the ester is too slow; to be conveniently measured. When theconc'entrations' j areincreased to 0:025 molar inester and 01 05 molar in sodiuni hydroxide the rate is such that 50%. of the esteri disappeared in 32.6'hours'. It should be noted ftha t this; rate is achieved with a concentration "of reactants that inf the 'case of homatropine methyl" bromide wouldspeed up the hydrolysis ten-fold and bring about a half-life of 13.2 seconds. Thus the rateof hydrolysis er compound No. 7] is 8400-fold' slower thanthat of homatropine methyl bro{ mide. Even at 37 C. the rate fofhydrolysisof compound" No. 7, at a concentration of 0.025 molarfand 0,0 5'molar sodium hydroxide is such that 50% hydro lys'isoccurslin about 10 hours, or 2700-fold slower thanhomatropine' methyl bromide at room temperature.

When other compounds, such as Nos, 13,; 17, 21, 25 and 28 were similarly tested 'for stability to hydrolysis under the conditions used for the testing of No. 7, it was found that all of these hydrolyze within the same approximate range of rates as No. 7, but many-fold more slowly than homatropine methyl bromide.

As noted above, many different types of acidshave previously 7 been used in preparing esters 'of tropinefl Among all these, no esters of the aliphatic acids or hyd roxy aliphatic acids with tropine'wer found-to have" any atropine-like action.

0 many aromatic and 'hydroxyjarom'atic'acidshave been In contrast," tropine esters of recognized by thoseskilled in the art of such compounds (see, e.g., Introduction to Chemical Pharmacology by R. B. Barlow, John Wiley & Sons, Inc., New York, 1956). In this text, on page 136, appears Table 36 in which are given the mydriatic activity of such esters of tropine.

It was therefore to be expected that tropine esters of all aliphatic monobasic acids would be lacking in atropine-like action. Contrary to this expectation, we found that tropine esters of this invention possess marked atropine-like activity, and in certain instances are several times as potent.

Examples of the new compounds and the methods of their preparation are as follows:

EXAMPLE 1 Diethyl acetyl tropinium citrate To a solution of 17.25 gms. (0.128 mole) of tropine in 100 ml. of anhydrous pyridine was added 19.6 gms. (0.145 mole) of diethylacetyl chloride. The mixture was boiled under reflux for 6 hours. It was then cooled, and the pyridine removed in a vacuum of 50-75 mm. with gentle heating. The solid residue was dissolved in chloroform. The chloroform solution was extracted with 10% hydrochloric acid. The aqueous acid solution was made basic, and the basic ester product was extracted with ether. The ether solution was dried and evaporated to dryness, leaving the product ester. This was treated with an eqnimolar quantity of citric acid, dissolved in ethanol. The citrate, of the composition shown, crystallized almost immediately.

on2-oH-orr= 02H; ant-o OOH CHxN onooocn .noo-coon CHz--CHCH: CzHs 11 0 OH This was recrystallized from ethanol and melted at 155 C.

EXAMPLE 2 A solution of 2.62 (0.011 mole) of diethyl acetyl tropine was made in 50 cc. of acetone. This free base was taken either from the appropriate stage of Example 1 or by liberation of the free base from the citrate salt of Example 1 with ammonia, extraction into ether, drying and evaporation of the ether extract to dryness. To the acetone solution of the free base was added an acetone solution, containing an excess of methyl bromide. Within a few minutes the methobromide started to crystallize. The mixture was allowed to stand for several hours. The crystallized solid was filtered, and additional product was obtained by evaporation of the filtrate. The yield was nearly quantitative. After recrystallization from acetone, the product melted at 318 C.

AnaIysis.-Calcd. for C H NO Br: Br, 23.90. Found: Br, 23.70.

EXAMPLE 3 Diethyl acetyl tropinium butobromide CH2CH CH, 0 0 115 cum n-04m ('JHO-b-o Br- CHz-CH CH2 C2H5 A solution of 4.13 gms. (.0124 mole) of diethyl acetyl tropine in acetone was prepared as in Example 2. This solution was boiled under reflux with 5 ml. of nbutyl bromide. On cooling the product crystallized. It was recrystallized from acetone and melted at 232 C.

Analysis.-Calcd. for C H NO B1: Br, 21.2%. Found: Br, 21.02%.

4 EXAMPLE 4 Di-n-pro'pyl acetyl tropine hydrochloride Tropine (11.12 gms.) was dissolved in ml. of anhydrous pyridine and to this solution was added 15.64- gms. of di-n-propyl acetyl chloride. The mixture wasrefluxed for 6 hours. This solution was then cooled and the pyridine removed in vacuo. The residue was dissolved in chloroform. The chloroform solution was washed with 10% hydrochloric acid to remove the residual trace of pyridine. The hydrochloride of the product ester soluble in chloroform and is not extracted from chloroform by hydrochloride acid. This is an unexpected prop-- erty. This unusual physical property is, in addition to the pharmacological action, a distinctive characteristic of most of the compounds of this invention.

The chloroform solution of the hydrochloride was dried over anhydrous calcium sulfate, and evaporated to dryness, leaving a semi-solid residue of product ester hydrochloride. This was recrystallized from chloroform-hexane mixture, M.P. 186 C.

Analysis.Calcd. for C H NO Cl: Found: Cl, 11.51%.

The citrate salt was prepared from the free base, analogously to the preparation of the citrate of Example 1. Recrystallized from ethanol it melts at 182 C.

Analysis.-Citric acid, calcd.: 41.8. Citric acid, found: 41.5.

EXAMPLE 5 Di-n-propyl acetyl tropinium methiodide EXAMPLE 6 Di-n-propyl acetyl tropinium methochloride The methiodide of Example 5 was boiled in methanol with a suspension of excess silver chloride, for six hours. The solid was filtered and the filtrate was evaporated to yield the above methochloride. It was recrystallized from acetone and'melted at 289 C.

Analysis.Calcd. for C H NO CI: Found: Cl, 11.15%.

EXAMPLE 7 Di-n-propyl acetyl. tropinium methobromide The free base of Example 4 was treated withmethyl bromide as in Example 2, to yield di-n-propyl acetyl tropinium methobromide. Recrystallized from boiling acetone it melts at 329 C. V V

Analysis.Calcd. for C17H32NO2B1': Br, 22.02%. Found: Br, 22.0%.

EXAMPLE 8 Di-n-propyl acetyl tropinium ethobromide The free base of Example 4 was boiled in acetonitrile with excess of ethyl bromide to yield the title compound, M.P. 299 C.

AnaIysis.-Calcd. for C H NO Brz Found: Br, 21.38%.

EXAMPLE 9 Di-n-propyl acetyl tropinium bum bromide 5 EXAMPLE- 10 Di-n-propylacetyl N-benzyl tropinium-chl oridex Following the procedure of example, with substitution of benzyl chloride for ethyl bromide, yielded the title teucy ofthis ester is-"10f to" 1S on" the 1 samefj basis" of that of atropine. Thus the pharmacological properties of these new compounds are totally unexpected.

Itmay be pointed out'that theminor structural change 5 involved in passing from compound No. 1 to compound i y s l' s: C NO Cl 9.25% No. 4 orcompound No. 19, has brought about a':qualita- F "3) 9 23 2 I tive differencein the physical. properties of the hydrof 2 no me esters uartemm chlorides of these'bases. Whereas, the hydrochloride of t a al formula q No. l 'is preferentially extracted by'dilute hydrochloric roplmum 5a 0 e g R acid from chloroform, the hydrochlorides of No. 4 and g No. 19, as well as the hydrochlorides of most of the other tertiary basic; esters are preferentially extracted by chloroa g form from dilute hydrochloric acid. Accompanying the HOOD-C R. change in such physical property there is a two hundred g to two thousand fold increase in atropine activity.

The operation of the invention herein disclosed is not R. tied to any theoretical basis for interpretation of the rewere made by varying the nature of R R R and R sults. From the novelty herein disclosed it will now heon the acid chloride to yield the tertiary amino alcohol come apparent to one skilled in the art that it is possible esters. Similarly R was varied by use of an appropriate to synthesize fatty acid esters of tropines, as well as of alkyl or aralkyl halide in the reaction typified by Exother amino alcohols, that can possess noteworthy and ample 8. The compounds thus prepared are tabulated, pe y high Pharmacologlcal activitiesincluding those already described in Examples 1-10 in- It W111 he understood t the foregoing description of elusive, in Table I. the nvention and the examples set forth are merely illus- TABLE tratlve of the principles thereof. Accordingly, the ap- Rl pended claims are to be construed as defining the inven-' CH tron within the full spirit and scope thereof. R/ CHz?H-CH2 We claim 1 CH0 RBNLCH 1. Members of the group conslstmg of B, (HHPCH: oH, cHoH,

H:- H- H: J: /C CH-OO-O- H CHsN R4 Ra-C s H's- H H:

Com ound A ti 1 IPO. R1 Ra R: R4 R; X M.P., Ati$ pin 1 OH: H OH: H H 00 1 1 155 0.1. 2 OH; H OH: H OH; Br 318 0.5. 3 OH; H OH: H 11-04139 Br 2333 0.02, 4 01H; H 0111 H H 01 186 20. 5 cm, H 02116 H OH, I 315 not tested 6 03H H 02H H CH: 01 289 1,000. 7 01H. H 02H! H CH3 Br 329 1,000. 8 C2115 H czHs B 02115 B! 299 2. 9 01H; H C Hs H Il-ClHD B! 245 2. 10 02H, H 02H. H C6H5CH9 01 250 0.25. 11 C1115 H CH: CHa C1 193 1. 12 (12H: H CH: CH3 CH: I 330 not tested H H 0H. OH; 0H. 01 299 13, H H 0H, CH3 11-04119 Br 2423 0.05.

CH; CH; OH. H H 257 0.1. CH: CH; OH: CH, I 336 nottested. CH3 CH3 CH3 CH3 Cl 322 0.2. 0H; CH3 CH3 III-04H! Br 254 0.05. 1% 8 3 5 CH 913707 H- l H n-CiHi H CH: 01 297 iti H III-(J3EE H Il-ClHQ Br 223 0.125. H 11-C3H1 H H 0011101 135 5. H n-CsH-l H OH: I 321 not tested. H 11-01111 H CH3 01 292 200. H 11-C3H1 H 11-04110 B! 251 1. H l-CsH7 H H 0011707 182 5. H l-CQH7 H CH; Br 324 200. 01H; H i-CaHv H I1-C4H9 Br 253 0.5.

1 These compounds solubility in water.

an ester of an hydroxy aromatic acid. The relative po- (all iodides) were not tested because they are of relatively sparing and wherein R is an alkyl radical having from 2 to 3 carbon atoms; R is a member of the group consisting of hydrogen and methyl; and X is an anion of a pharmaceutically acceptable acid.

2. Di-(n-propyl)-acetyl-tropinium-hydrochloride. 3. (n-Propyl) (n-butyl)-acetyl-tropinium-acid citrate. 4. (n-Propyl) (isobutyl)-acetyl-tropinium-acid citrate. 5. Di-n-propyl-acetyl-tropinium-methochloride.

6. Di-n-propyl-acetyl-troPinium-methqbgomide. OTHER REFERENCES (n'PmPYl) (n'butyl) acetyl'u'opmmm'methochlo Gyermek et aL: Chem. Abstracts, vol. 47, col. 7111 n V (n'PmPyn (lsobutyl) 'acetyl'tmplmum'methobm Nadbr et aL: Chem. Abstracts, vol. 48, col. 5353 5 1954 References Cited in the file of this patent (lgrsygrmek at 2.1.: Chem. Abstracts, vol. 48, col. 8938 UNITED STATES PATENTS Rosenblum et aL: Chem. Abstracts; vol. 49, col. 6283 2,828,312 Johnston et a1. Mar. 25, 1958 (1955). 

1. MEMBERS OF THE GROUP CONSISTING OF 